Treatment and Medication Goutttt

7/29/2019 Treatment and Medication Goutttt

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TREATMENT AND MEDICATION

Approach Considerations

Gout is managed in the following 3 stages:

Treating the acute attack

Providing prophylaxis to prevent acute flares Lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of

urate crystalsIn 2012, the American College of Rheumatology (ACR) published guidelines on the treatment andprophylaxis of acute gouty arthritis and the management of hyperuricemia.[95, 96]

As a general rule, asymptomatic hyperuricemia should not be treated, though ultrasonographic studieshave demonstrated that urate crystal deposition into soft tissues occurs in a minority of patients withasymptomatic hyperuricemia.[89, 88]Patients with levels higher than 11 mg/dL who overexcrete uric acid areat risk for renal stones and renal impairment; therefore, renal function should be monitored in theseindividuals.[30]

Tophi should not be surgically removed unless they are in a critical location or drain chronically. Surgerymay be indicated for tophaceous complications, including infection, joint deformity, compression (eg,

cauda equina or spinal cord impingement), and intractable pain, as well as for ulcers related totophaceous erosions. Delayed healing is noted in 50% of patients.

Treatment of the acute phase of pseudogout is identical to that of acute gout. In patients with idiopathicpseudogout, a deterrent regimen of colchicine may be used. If an underlying metabolic problem isresponsible for pseudogout, the arthritis may be cured when the underlying problem is addressed.

Treatment of Acute Attacks

The temptation to treat patients without a proven diagnosis must be resisted. Septic arthritis may clinicallyresemble gout or pseudogout, and unrecognized septic arthritis can lead to loss of life or limb.Distinguishing septic arthritis from crystal-induced arthritis is not possible without an examination of jointfluid.

Acute treatment of proven crystal-induced arthritis is directed at relief of the pain and inflammation.Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine, and adrenocorticotropichormone (ACTH) are treatment options. The choice is based primarily on whether the patient has anyconcomitant health problems (eg, renal insufficiency or peptic ulcer disease). Colchicine, a classictreatment, is now rarely indicated.

When comorbid conditions limit the use of NSAIDs or colchicine, a preferred option may be an intra-articular steroid injection, particularly when a large, easily accessible joint is involved. Septic arthritis mustbe reasonably excluded.

Therapy to control the underlying hyperuricemia generally is contraindicated until the acute attack iscontrolled (unless kidneys are at risk because of an unusually heavy uric acid load). Starting therapy tocontrol hyperuricemia during an acute attack may intensify and prolong the attack. If the patient has beenon a consistent dosage of probenecid or allopurinol at the time of the acute attack, however, the drug

should be continued at that dosage during the attack.

Furthermore, control of hyperuricemia generally is not pursued for a single attack. If attacks are recurrentor evidence of tophaceous or renal disease is present, therapy for control of hyperuricemia is indicated. [97,

98, 99]

Nonsteroidal anti-inflammatory drugs

NSAIDs are the drugs of choice in most patients with acute gout who do not have underlying healthproblems. Although indomethacin is the NSAID traditionally chosen for acute gout, most of the other



NSAIDs can be used as well. Select an agent with a quick onset of action. Do not use aspirin, because itcan alter uric acid levels and potentially prolong and intensify an acute attack. Cyclooxygenase-2 (COX-2)inhibitors have been used with success, but patients may require higher dosages than are typicallyused.[100]

Avoid NSAIDs in patients with a history of peptic ulcer disease or gastrointestinal (GI) bleeding, thosewith renal insufficiency or abnormal hepatic function, those taking warfarin (a selective COX-2 inhibitor

can be used), and those in the intensive care unit (ICU) who are predisposed to gastritis. Limit NSAID usein elderly patients, because of the potential for adverse central nervous system (CNS) effects. UseNSAIDs cautiously in patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.

To control the acute attack, NSAIDs are prescribed at full dosage for 2-5 days. Once the acute attack iscontrolled. the dosage is reduced to approximately one half to one fourth of that amount. Taper thedosage over approximately 2 weeks. Gout symptoms should be absent for at least 2 days before theNSAID is discontinued.

Colchicine

Although colchicine was once the treatment of choice for acute gout, it is now less commonly used thanNSAIDs because of its narrow therapeutic window and risk of toxicity.[101, 102] To be effective, colchicine

therapy is ideally initiated within 36 hours of onset of the acute attack. When used for acute gout inclassic hourly dosing regimens (no longer recommended), colchicine causes adverse GI effects,particularly diarrhea and vomiting, in 80% of patients.

Dosing recommendations for colchicine in the treatment of acute gout have undergone modifications asawareness of its toxicities has increased. Newer recommendations trend toward lowered daily andcumulative doses.[103, 101] .

The regimen currently favored consists of 1.2 mg of colchicine, followed by 0.6 mg 1 hour later to initiatetreatment of the early gout flare. In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Terkaltaub et al found that this regimen yielded both maximum plasma concentration andearly gout flare efficacy comparable with those of high-dose colchicine (4.8 mg total over 6 hours), with asafety profile indistinguishable from that of placebo.[104]

Data from 7 separate drug-to-drug interaction (DDI) studies suggests colchicine dose reductions of 33-66% for treatment of acute gout and 50-75% for prophylaxis when colchicine is given in combination withthe extended-release calcium channel blockers verapamil and diltiazem or with the numerous P-gp and/or CYP3A4 inhibitors (eg,clarithromycin and cyclosporine); in addition, patients should avoid grapefruit juice.Dosages of colchicine did not have to be adjusted when the drug was used in combination withazithromycin.[105]

Colchicine should generally be avoided if the glomerular filtration rate (GFR) is lower than 10 mL/min, andthe dose should be decreased by at least half if the GFR is lower than 50 mL/min. Colchicine should alsobe avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.

A clinical response to colchicine is not pathognomonic for gout. Responses may also occur in patientswith pseudogout, sarcoid arthropathy, psoriatic arthritis, or calcific tendonitis.

In February 2008, the US Food and Drug Administration (FDA) ruled that intravenous (IV) colchicine canno longer be produced or shipped in the United States, because of its toxicities. Consequently, IVcolchicine is no longer advocated for the treatment of acute gout in the United States .[106]

Corticosteroids

Corticosteroids can be given to patients with gout who cannot use NSAIDs or colchicine. Steroids can begiven orally, IV, intramuscularly (IM), or intra-articularly. Using parenteral corticosteroids confers noadvantage unless the patient cannot take oral medications.



Prednisone can be given at a dose of approximately 40 mg for 1-3 days, which is then tapered over approximately 2 weeks (tapering more rapidly can result in a rebound flare). Monitor closely for corticosteroid effects. If treatment continues for more than 2 weeks, consider measures to preventosteoporosis.

Intra-articular long-acting (depot) corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids. Ensuring that the joint is not infected before

injecting intra-articular corticosteroids is particularly important.

An alternative to corticosteroid administration is to give ACTH (40 IU subcutaneously, with repeat dosingas needed) to induce production of corticosteroid by the pat ient’s own adrenal glands. Such a regimendoes not depend on the patient for proper tapering of prednisone.

Combination therapy

If the patient does not have an adequate response to initial therapy with a single drug, ACR guidelinesadvises that adding a second appropriate agent is acceptable. Using combination therapy from the start isappropriate for an acute, severe gout attack, particularly if the attack involves multiple large joints or ispolyarticular. Acceptable regimens include any of the following, in full or prophylactic doses asappropriate[96] :

Colchicine plus NSAIDs Oral corticosteroids plus colchicine

Intra-articular steroids plus colchicine or NSAIDs

Treatment of Chronic Gout

When a patient experiences a first attack of gout, any medication regimens that may have contributed tothe gout attack must be altered, and any predisposing medical conditions or habits must beaddressed.[107] Patients should be instructed to go on a diet if obese, to stop drinking beer, and to avoidpurine-rich foods.

In many cases, patients who have a first attack of gout should undergo therapy with agents that lower uricacid, given the high risk for further inflammatory attacks and the potential for destructive tophaceousdeposition in the bone, synovium, and kidney, even without episodes of acute inflammation. If the firstattack is not severe, however, some rheumatologists advocate waiting for a second attack before

initiating such therapy; not all patients experience a second attack, and some patients may requireconvincing that they need life-long therapy.

The risk of a second attack of gout after the first attack is 62% after 1 year, 78% after 2 years, and 93%after 10 years. The decision to begin therapy depends partly on the baseline serum uric acid levels (>9mg/dL denotes a higher risk for recurrent gouty arthritis and tophi).

ACR guidelines recommend pharmacologic urate-lowering therapy for patients with gout who have 1 or more tophi on clinical examination or imaging study or have frequent attacks of acute gouty arthritis (≥2attacks per year). Less robust evidence supports pharmacologic therapy for patients with chronic kidneydisease of stage 2 or worse or a past history of urolithiasis .[95]

Long-term management of gout is focused on lowering uric acid levels. The goal of therapy is to reduceserum uric acid levels to below 6 mg/dL, at minimum. In many cases, lowering uric acid levels to less than

5 mg/dL is necessary to improve the signs and symptoms of gout. ACR guidelines recommend that oncepalpable tophi and all acute and chronic gout symptoms have resolved, serum uric acid levels should bemaintained below 6 mg/dL indefinitely.[95]

In contrast, Perez-Ruiz et al have proposed that once dissolution of existing urate crystals has beenachieved, less stringent control may suffice to prevent formation of new crystals.[108] In their prospectivecohort study of 211 patients from whom urate-lowering therapy was withdrawn either after 5 years if notophus was present at baseline or 5 years after resolution of the last tophus, no patient who maintainedan average serum urate level lower than 7 mg/dL developed a crystal-proven recurrence of gout.



Avoiding the use of medications that elevate uric acid in patients with gout is prudent. Thus, in patientswith hypertension, other agents are preferable to a thiazide diuretic, provided that blood pressure can bemanaged easily with a single drug. Low-dose aspirin is also uricosuric. The angiotensin-receptor blocker (ARB) losartan should be considered, because it is uricosuric at 50 mg/day. However, medications thatelevate uric acid can still be used, if required, by making appropriate adjustments of allopurinol or probenecid doses.

Urinary excretion amounting to less than 800 mg per 24-hour period on an unrestricted diet is consideredunderexcretion. Underexcreting patients are candidates for uricosuric therapy with probenecid. Thedosage is increased at monthly intervals until the uric acid level is lowered to target. Urinary alkalization(eg, with potassium citrate) and ingestion of copious amounts of fluid are adjunctive recommendations.

In patients with gout who have renal disease, ACR guidelines recommend xanthine oxidase inhibitor therapy with either allopurinol or febuxostat as the first-line pharmacologic approach. Probenecid can beused in patients who have contraindications to or are intolerant of at least 1 of those first-line agents, or itmay be combined with a xanthine oxidase inhibitor if the inhibitor does not lower uric acidsufficiently.[95] Probenecid could also be used for those patients who consider the risks of xanthine oxidaseinhibitors to be too high.

The ACR advises, however, that monotherapy with probenecid is not a first-line choice in patients with a

creatinine clearance of less than 50 mL/min.

[95]

In addition, drug interactions may occur with probenecid(see Medication).

Prophylaxis

Because allopurinol, febuxostat, and probenecid change serum and tissue uric acid levels, they mayprecipitate acute attacks of gout. To reduce this undesired effect, colchicine or low-dose NSAID treatmentis provided for at least 6 months. In patients who cannot take colchicine or NSAIDs, low doses of prednisone can be considered. When used prophylactically, colchicine can reduce such flares by85%.[109] Patients with gout may be able to abort an attack by taking a single colchicine tablet at the firsttwinge of an attack.

The standard dosage of colchicine for prophylaxis is 0.6 mg twice daily, but lower dosages have alsobeen suggested. Significant dosage reduction is critical for patients who are also taking calcium channelblockers (eg, verapamil or diltiazem) and any of the large number of P-gp or CYP3A4 inhibitors (eg,clarithromycin or cyclosporine). In patients with renal insufficiency, the dosing frequency may have to bedecreased to once daily or every other day.

Adverse GI effects are uncommon with this dosage, occurring in only 4% of patients. This stands incontrast to the 80% risk of adverse GI effects with the classic hourly colchicine regimen for the treatmentof acute gout.

Even in prophylactic doses, however, long-term use of colchicine can lead to marrow toxicity and toneuromyopathy, with elevated levels of creatine kinase and resulting muscle weakness. Colchicine-induced neuromyopathy is a particular risk in patients with renal insufficiency.[110]

If the patient develops a gout flare after beginning therapy with a uric acid –lowering agent, the agentshould not be discontinued, because discontinuance will only cause another flux in the uric acid level,which may prolong and intensify the attack.

Allopurinol

Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Approximately 3-10% of patients taking allopurinol develop symptoms of intolerance, such as dyspepsia, headache, diarrhea, or pruritic maculopapular rash.

Less frequently (1% of cases), patients taking allopurinol can develop severe allopurinol hypersensitivitysyndrome, which carries a mortality of 20-30%.[111]Features of this syndrome include fever, toxic epidermal



necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, andvasculitis. Corticosteroids are often used to treat severe allopurinol hypersensitivity syndrome.

Severe allopurinol hypersensitivity syndrome is more likely to occur in patients with renal insufficiency,those who are taking a thiazide diuretic, and those started on allopurinol at a dosage of 300 mg/day . [112] Inaddition, strong associations have been found between severe allopurinol hypersensitivity reactions andcarriage of the HLA –B*5801 allele.[113]

ACR guidelines recommend considering screening for HLA –B*5801 carriage, using a polymerase chainreaction –based test, in selected high-risk patients before starting allopurinol. Patients at particularly highrisk are known to include those of Han Chinese or Thai descent; Koreans are also at risk, if they havestage 3 or worse chronic kidney disease.[95] It is unclear whether such precautions are necessary with a100-mg starting dose of allopurinol. Additionally, availability of this test may be an issue.

Severe allopurinol hypersensitivity syndrome may present as Stevens-Johnson syndrome or as drug rashwith eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome affects the liver, kidney,and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after initiation of allopurinol. Theunderlying mechanism is thought to be a cell-mediated immune reaction to allopurinol and its metabolites. Although the frequency is only is 0.4%, the rate of organ failure and death is high. Treatment is with IV N-

acetylcysteine and steroids.

Allopurinol should immediately be discontinued in patients who develop pruritus or a rash consistent withallopurinol hypersensitivity.

In most patients, start allopurinol at 100 mg/day (50 mg/day in patients with renal insufficiency). Stamp etal have proposed that the risk of allopurinol hypersensitivity may be reduced by starting allopurinol at adose of 1.5 mg per unit of estimated GFR.[114]

Adjust the dosage upward every 2-5 weeks according to the uric acid level until the goal of a uric acidlevel of 6 mg/dL or less is achieved. Once the target uric acid level has been achieved and maintained for 6 months, discontinue colchicine prophylaxis, unless the patient has 1 or more tophi on clinical exam.

Previously, adjusting the allopurinol maintenance dosage to the creatinine clearance rate wasrecommended for patients with renal insufficiency. However, Vázquez-Mellado et al found no increase inthe prevalence of adverse reactions to allopurinol in patients who were started at an adjusted dosage butsubsequently had their dosage raised to meet therapeutic targets.[115]

ACR guidelines advise that the dosage of allopurinol can be raised above 300 mg/day, even in patientswith renal impairment, provided that the patient receives adequate education and monitoring for drugtoxicity (including measurement of transaminase levels). The maximum dosage of allopurinol approved bythe US Food and Drug Administration (FDA) is 800 mg/day,[95] , but the maximum dosage should be lower in patients with chronic kidney disease.

Beware of drug interactions. For example, allopurinol prolongs the half-life of azathioprine and 6-mercaptopurine. It enhances the bone marrow toxicity of cyclophosphamide. Patients taking concomitantampicillin are at an increased risk of rash.

Allopurinol can be used in combination with probenecid. However, note that probenecid increases theexcretion of allopurinol.

In a retrospective 24-month study of gout patients who had been prescribed allopurinol, Riedel et al foundthat only 18% of them filled all their prescriptions throughout the entire follow-up period and thus werepresumably compliant; 10.4% filled only a single prescription.[116] In contrast, Rees et al reported that whenpatients receiving urate-lowering therapy were given a predominantly nurse-delivered intervention thatincluded education and individualized lifestyle advice, 92% achieved target serum uric acid levels at 1year .[117]

Febuxostat

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Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol inpatients with gout.[118, 119] Febuxostat is administered orally and is metabolized mainly in the liver. Incontrast, allopurinol and its metabolites are excreted primarily by the kidney. Therefore, febuxostat can beused in patients with renal impairment with no dosage adjustment.[120] It is more expensive thanallopurinol.

The CONFIRMS trial demonstrated the efficacy and safety of febuxostat in lowering hyperuricemia. By 6

months, the primary endpoint—a serum uric acid level of less than 6.0 mg/dL—was achieved in 45% of subjects on febuxostat 40 mg/day, 67% on febuxostat 80 mg/day, and 42% on allopurinol. In subjectswith renal impairment, the primary endpoint was achieved in 50% of subjects on febuxostat 40 mg/day,72% on febuxostat 80 mg/day, and 42% on allopurinol. Adverse event rates were low and similar in allgroups.[121]

In patients aged 65 years or older, the primary endpoint was achieved in 62% on febuxostat 40 mg/day,82% on febuxostat 80 mg/day, and 47% on allopurinol. These figures remained essentially unchanged insubjects with mild-to-moderate renal impairment.[122]

In African-American subjects, the primary endpoint was reached in 47% on febuxostat 40 mg/day, 68%on febuxostat 80 mg/day, and 43% on allopurinol. Similar rates were seen in subjects with renalimpairment.[123] Adverse event rates in both subgroups were comparable with those in the overall trial.

The efficacy and safety of febuxostat in women was demonstrated in the CONFIRMS trial and in 2 other trials comparing febuxostat and allopurinol: FACT (Febuxostat Versus Allopurinol Controlled Trial) and APEX (Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat). Achievement of a uric acidlevel below 6.0 mg/dL rose with increasing daily doses of febuxostat doses, from 54.3% in patientsreceiving 40 mg to 100% in those receiving 240 mg, compared with 45.9% with allopurinol. Results weresimilar in subjects with renal impairment.[124]

Uricase

Nonrecombinant urate-oxidase (uricase) is used in Europe to prevent severe hyperuricemia induced bychemotherapy in patients with malignancies, as well as in selected patients with treatment-refractory gout.Short-term use of such agents in patients with severe tophaceous gout could debulk the total-body urateload, allowing maintenance with probenecid or allopurinol.

In 2009, the FDA approved recombinant uricase (rasburicase) for the prevention of tumor lysis syndrome.However, it is highly immunogenic and may cause anaphylaxis.[125]

In 2010, a polyethylene-glycol –conjugated uricase (pegloticase) was approved by the FDA for gout.Pegloticase, which enzymatically catalyzes the oxidation of uric acid to allantoin, is an IV biologic agent tobe considered when adjustment of contributing medications (eg, diuretics) and treatment with allopurinol,febuxostat, and uricosuric agents are insufficient to achieve appropriate reduction of serum uric acidlevels.[95]

The European Medicines Agency (EMA) is now weighing approval of pegloticase in Europe. Approvalwas recommended by an expert advisory committee.[126]

Adverse effects of pegloticase include anaphylaxis, infusion reactions, gout flares, and exacerbation of congestive heart failure. At present, substantial expense compromises its cost-effectiveness as an initial

approach.[127] . The ACR guidelines do not recommend pegloticase as a first-line approach.

Other therapeutic options

Benzbromarone is an effective uricosuric agent available on a restricted basis only outside the UnitedStates. However, it has been withdrawn because it causes fulminant hepatotoxicity.

Vitamin C, with its uricosuric effect, may reduce the serum concentration of uric acid. In one study, 500mg/day for 2 months reduced uric acid by a mean of 0.5 mg/dL in patients without gout .[128] However, gout



patients appear to be less responsive to such a low dose of ascorbate. Vitamin C treatment should beavoided in patients with nephrolithiasis, urate nephropathy, or cystinuria.

In an open-label pilot study of 10 patients with refractory acute gout treated with the interleukin (IL)-1antagonist anakinra, pain was substantially reduced in all patients within 2 days, without side effects.Clinical signs of inflammation had disappeared in 9 of 10 patients by day 3 of treatment.[129]

The lipid-lowering drug fenofibrate, a fibric acid derivative, lowers serum uric acid levels while reducingvery-low-density lipoprotein (VLDL), total cholesterol, and triglyceride levels.[130] However, the creatininelevel increases, and all effects are negated once the drug has been discontinued.[125]

Canakinumab

In 2010, an 8-week, single-blind, double-dummy, dose-ranging study showed that the selective IL-1βantibody canakinumab yielded fast and lasting relief of pain in patients with acute gouty arthritis flaresrefractory to treatment with NSAIDs or colchicine.[131] However, in June 2011, canakinumab was deniedapproval by the FDA.[132] (See FDA Panel Says No to Canakinumab for Gout Attacks.)

Diet and Activity

Because uric acid is a breakdown product of purine, high-purine foods should be either avoided or

consumed only in moderation. Foods very high in purines include organ meats such as sweetbreads (eg,pancreas and thymus), smelt, sardines, and mussels. Foods moderately high in purines includeanchovies, trout, haddock, scallops, mutton, veal, liver, bacon, salmon, kidneys, and turkey.

Purines are found in all protein foods. All sources of purines cannot and should not be eliminated.

Overall, purine restriction generally reduces serum uric acid levels by no more than 1 mg/mL, with modestimpact, and diets with very low purine content are not palatable. Diet modifications alone are rarely ableto lower uric acid levels sufficiently to prevent accumulation of urate, but they may help lessen the triggersof acute gout attacks.

Patients with gout should avoid excess ingestion of alcoholic drinks, particularly beer, because alcoholuse elevates uric acid levels and thus can precipitate attacks of gout. Indeed, heavy drinkers are muchmore likely to have recurrent gout attacks, even with allopurinol therapy. Moderate wine intake is not

associated with increased development of incident gout,

[1]

but excesses of any form of alcohol in goutpatients are associated with acute gout flares.

Patients should avoid sodas and other beverages or foods sweetened with high-fructose corn syrup. Theyshould also limit their use of naturally sweet fruit juices, table sugar, and sweetened beverages anddesserts, as well as table salt.[95] . Patients taking colchicine should avoid grapefruit and grapefruit juice.

Maintaining a high level of hydration with water (at least 8 glasses of liquids per day) may be helpful inavoiding attacks of gout. In view of the association of gout with atherosclerosis, the diagnosis of gout mayafford a particularly good opportunity for the clinician to advise a low-cholesterol, low-fat diet if such a dietis otherwise appropriate for the patient. Although a diet of this type may help uric acid levels, such adviceshould be given primarily to help prevent atherosclerosis.

Weight reduction in patients who are obese can improve hyperuricemia. Ketosis-inducing diets (eg,

fasting) should be avoided, however.

Because acute attacks are already sufficiently limiting of activity, additional limitations of activity are notnecessary. The patient should avoid trauma to the affected joint; otherwise, they should be active.

Consultations

Rheumatologists should be involved in the care of patients with difficult gout, as advised in the ACRguidelines. They can establish the diagnosis with arthrocentesis and synovial fluid analysis for crystals.They also are skilled in the management of this disorder, and consultation may be helpful for patients with

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an acute gout attack that does not respond to NSAIDs within 2 days or to colchicine within 1 day, as wellas for patients with refractory hyperuricemia.

Rheumatology or orthopedic consultation is indicated for any patient with septic arthritis or for any patientin whom a septic arthritis cannot be ruled out.

Long-Term Monitoring

After diagnosis and treatment of an acute gouty arthritis episode, the patient should return for a follow-upvisit in approximately 1 month to be evaluated for therapy to lower serum uric acid levels.

If uric acid –lowering therapy is begun, patients should be seen within 2 weeks to ensure that no untowardtoxicity has developed and then every 1-2 months while medication dosages are adjusted to achieve thetarget uric acid level of 5-6 mg/dL. Once this level is achieved and maintained, patients can be seenevery 6-12 months and their serum uric acid monitored to help assess efficacy and adherence.

MEDICATION

Medication Summary

Acute inflammation due to gout can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs),corticosteroids, or colchicine. NSAIDs are the most commonly used drugs in acute gout.

Over the long term, gout is treated by decreasing tissue stores of uric acid with the xanthine oxidaseinhibitors allopurinol or febuxostat or with the uricosuric agent probenecid. Because agents that lower uricacid can precipitate attacks of gout, low-dose colchicine is typically used as prophylaxis (usually for 6months) when such therapy is initiated.

If these measures, along with adjustment of contributing medications (eg, diuretics), do not result inappropriate reduction of serum uric acid levels, uric acid−lowering treatment is escalated asrecommended in the 2012 American College of Rheumatology (ACR) gout guidelines.[95, 96]

Other agents lower uric acid levels as a secondary effect. The angiotensin-receptor blocker (ARB)

losartan is moderately uricosuric at 50 mg/day. The lipid-lowering agent fenofibrate reduces serum urate19% and increases clearance by 36% at 200 mg/day.[39]

NSAIDs

Class Summary

As a class, NSAIDs are the drugs most widely used to treat the pain and inflammation of acute goutattacks in patients who can safely take these medications. Although NSAID effects on pain tend to bepatient-specific, naproxen and indomethacin are common choices. Nevertheless, the choice of an NSAIDis a matter more of habit than of science. Use of concomitant gastric protection with misoprostol or consideration of a cyclooxygenase-2 (COX-2) –specific NSAID might be considered if the patient hasgastrointestinal (GI) risk or is older than 51 years.

To control the attack as quickly and safely as possible (recalling that it takes 5 half-lives to reach steady

state), consider using an NSAID with a short half-life (eg, ketoprofen, ibuprofen, or diclofenac). Use themaximum dosage of NSAID, and taper over approximately 10-14 days, depending on patient response.

View full drug information

Naproxen (Anaprox, Naprelan, Naprosyn)

Naproxen is used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain bydecreasing activity of the enzyme cyclooxygenase, resulting in prostaglandin synthesis.

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Ketoprofen

Ketoprofen is used for the relief of mild-to-moderate pain and inflammation. Small doses are initiallyindicated in small and elderly patients and in those with renal or liver disease. Individual doses greater

than 75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observethe patient for response.


Diclofenac (Voltaren XR, Cataflam, Arthrotec)

Diclofenac inhibits prostaglandin synthesis by decreasing activity of the enzyme cyclooxygenase, which inturn decreases formation of prostaglandin precursors.


Indomethacin (Indocin)

Indomethacin has been the NSAID traditionally used to treat acute inflammation in gout, though other NSAIDs are effective in this setting as well. Like all NSAIDs, indomethacin blocks cyclooxygenase andthereby reduces the generation of prostaglandins.


Celecoxib (Celebrex)

Unlike most NSAIDs, which inhibit both COX-1 and COX-2, the selective COX-2 inhibitor celecoxib offersthe possibility of relieving inflammation and pain, but with a lower risk of GI side effects. It has beensuggested that COX-2 expression in monocytes is induced in response to urate crystals.

Several studies have found that selective COX-2 inhibitors are comparable to other NSAIDs for treatingacute gouty arthritis. However, celecoxib requires particularly high doses to provide pain relief comparable to that provided by indomethacin in acute gout .[100]

Selective COX-2 inhibitors may increase the risk of cardiac disease; 1 drug in this class, rofecoxib, hasalready been removed from the market for this reason. Celecoxib is currently under investigation for associated risk of accelerated cardiac disease. Curiously, the risk appears to be associated with ingestionof 200 mg twice daily, but not with ingestion of 400 mg once daily.

Uricosuric Agents

Class Summary

Uricosuric agents lower uric acid levels by inhibiting renal tubular reabsorption of uric acid, therebyincreasing net renal excretion of uric acid. These agents increase the risk of renal stones, with about a 9-10% risk for probenecid. They should not be started during an attack of acute gouty arthritis. The goal of

therapy is to lower serum uric acid to approximately 5-6 mg/dL without causing renal stones.


Colchicine (Colcrys)

Colchicine inhibits microtubules and may thereby inhibit phagocytosis, neutrophil mobility, andchemotaxis. It also may inhibit generation of prostaglandins. The traditional approach of giving colchicineuntil vomiting or diarrhea appears is not appropriate; these are signs of toxicity. Instead, 1.2 mg is given

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orally, followed by 0.6 mg after 1 hour. Dose reduction is required for coingestion of interacting drugs (eg,P-gp or CYP3A4 inhibitors).


Probenecid

Probenecid lowers tissue stores of uric acid by increasing net renal excretion of uric acid throughinhibition of tubular reabsorption. Some authorities recommend alkalizing the urine when startingprobenecid to reduce the risk for renal stone formation. Probenecid is indicated for long-termmanagement of hyperuricemia associated with gout.

Corticosteroids

Class Summary

Corticosteroids are potent and effective anti-inflammatory drugs that can be used to treat acute gout inpatients who cannot tolerate NSAIDs or colchicine. They can be given orally, intramuscularly (IM),intravenously (IV), or intra-articularly. Adrenocorticotropic hormone (ACTH) also acts in gout, in part byinducing adrenal steroids. No intrinsic advantage to treating with IV corticosteroids exists unless thepatient cannot take oral medications.

The short-burst corticosteroid regimen used to treat an acute flare of gout is generally well tolerated.Nevertheless, patients may experience the adverse effects seen with long-term steroid use.

In patients with only 1 or 2 involved joints, intra-articular corticosteroids are a safe and effective treatmentoption, once infection has been excluded. Water-soluble steroids (eg, dexamethasone) are teleologicallyinappropriate for use as a depot steroid treatment.


Prednisone

Oral prednisone can be given to abort an attack of gout. By reversing increased capillary permeability andsuppressing polymorphonuclear leukocyte (PMN) activity, this agent may decrease inflammation. Steroid

dose packs that clearly label the dose to be taken each day can be convenient for some patients.


Triamcinolone (Aristocort)

Intra-articular use is considered by some as the treatment of choice for pseudogout and for acute goutyattacks in patients who cannot be given NSAIDs, colchicine, or high-dose systemic corticosteroids.


Corticotropin (HP Acthar Gel, Acthar Gel)

Corticotropin stimulates endogenous production of corticosteroids and directly and rapidly acts onperipheral leukocyte activation. It decreases inflammation by suppressing migration of PMNs andreversing increased capillary permeability.

Xanthine Oxidase Inhibitors

Class Summary

Inhibition of xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine, reduces thesynthesis of uric acid without disrupting the biosynthesis of vital purines. This results in the reduction of the tissue stores of uric acid. The goal of therapy is to lower the serum uric acid level to approximately 5-6

http://reference.medscape.com/drug/probenecid-342832




http://reference.medscape.com/drug/prednisone-intensol-342747




http://reference.medscape.com/drug/aristocort-kenalog-iv-triamcinolone-342748




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mg/dL. These agents should not be started during an attack of acute gouty arthritis without adequatecontrol of the gouty inflammation.


Allopurinol (Zyloprim, Aloprim)

Allopurinol reduces production of uric acid, thereby allowing the body to dispose of excess uric acidstores. It is the most effective therapy for lowering serum uric acid. Most patients achieve the target uricacid level of 5 mg/dL at a dosage of 300-400 mg/day. A lower dosage is used if renal insufficiency ispresent.


Febuxostat (Uloric)

Febuxostat is a potential alternative to allopurinol.[118, 119] Like allopurinol, febuxostat is a xanthine oxidaseinhibitor that prevents uric acid production and lowers elevated serum uric acid levels. Unlike allopurinol,it is a thiazolecarboxylic acid derivative, not a purine base analogue. Febuxostat physically blocks thechannel to the molybdenum-pterin active site of xanthine oxidase and is metabolized by liver oxidation

and glucuronidation.[39]

Common adverse events include upper respiratory tract infections, arthralgias, diarrhea, headache, andliver function abnormalities. Atrioventricular block or atrial fibrillation and cholecystitis also have beenreported.[133] As with other uricosuric agents, initiation of febuxostat may precipitate gouty attacks.[39, 133]

Rheumatologics, Other

Class Summary

Uricase facilitates conversion of urate to allantoin. Unlike uric acid, allantoin is soluble and easily excretedby the kidneys. Thus, hyperuricemia is reduced, with little risk of acute kidney injury.


Pegloticase (Krystexxa)

Pegloticase is a pegylated uric acid –specific enzyme that is a polyethylene glycol conjugate of recombinant uricase. It achieves its therapeutic effect by catalyzing oxidation of uric acid to allantoin,thereby lowering serum uric acid levels. Pegloticase is indicated for gout in adults refractory toconventional therapy (ie, when serum uric acid levels have not normalized and either signs andsymptoms are inadequately controlled with xanthine oxidase inhibitors or uricosurics at maximumappropriate doses or xanthine oxidase inhibitors are contraindicated).

The dosage is 8 mg IV every 2 weeks. Complications include anaphylaxis, infusion reactions, flare of goutattacks in 63-86% of patients and nephrolithiasis in 13-14%, along with arthralgias, nausea, dyspepsia,muscle spasms, pyrexia, back pain, diarrhea, and rash.[134, 135] Glucose-6-phosphate dehydrogenase(G6PD) deficiency is a contraindication.[135]

Corticotropic Hormones

Class Summary

Corticotropic hormones stimulate synthesis and release of corticosteroid hormones. They are principallyused in diagnostic tests to differentiate primary adrenal insufficiency from secondary adrenal insufficiency.They have limited therapeutic value in conditions responsive to corticosteroid therapy, for which acorticosteroid should be the drug of choice.


http://reference.medscape.com/drug/zyloprim-aloprim-allopurinol-342811




http://reference.medscape.com/drug/uloric-febuxostat-345048




http://reference.medscape.com/drug/krystexxa-pegloticase-999601




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Cosyntropin (Cortrosyn, Synthetic ACTH)

Cosyntropin is an adrenocorticotropic hormone (corticotropin) that stimulates the production and releaseof endogenous steroids. It is an effective treatment of acute crystal-induced arthritis in postoperativepatients and in other patients who cannot take oral medications.




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Treatment and Medication Goutttt